The Impact of Synbiotic Treatment on the Levels of Gut-Derived Uremic Toxins, Inflammation, and Gut Microbiome of Chronic Kidney Disease Patients-A Randomized Trial.

OBJECTIVE: Altering dysbiotic gut flora through synbiotic supplementation has recently been recognized as a potential treatment strategy to reduce the levels of gut-derived uremic toxins and decrease inflammation. Assessing its efficacy and safety has been the main goal of our randomized, double-blind, placebo-controlled study. METHODS: A total of 34 nondialyzed chronic kidney disease patients, aged ≥18 years, with an estimated glomerular filtration rate between 15 and 45 mL/minute, were randomized either to an intervention group (n = 17), receiving synbiotic (Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium lactis, 32 billion colony forming units per day plus 3.2 g of inulin), or control group (n = 17), receiving placebo during 12 weeks. The impact of treatment on the dynamic of serum levels of gut-derived uremic toxins, total serum indoxyl sulfate, p-cresyl sulfate, and trimethylamine N-oxide, was defined as the primary outcome of the study. Secondary outcomes included changes in the stool microbiome, serum interleukin-6 levels, high-sensitivity C-reactive protein, estimated glomerular filtration rate, albuminuria, diet, gastrointestinal symptom dynamics, and safety. Serum levels of uremic toxins were determined using ultraperformance liquid chromatography. The stool microbiome analysis was performed using the 16S ribosomal ribonucleic acid gene sequencing approach. RESULTS: Synbiotic treatment significantly modified gut microbiome with Bifidobacteria, Lactobacillus, and Subdoligranulum genera enrichment and consequently reduced serum level of indoxyl sulfate (ΔIS -21.5% vs. 5.3%, P < .001), improved estimated glomerular filtration rate (ΔeGFR 12% vs. 8%, P = .029), and decreased level of high-sensitivity C-reactive protein (-39.5 vs. -8.5%, P < .001) in treated patients. Two patients of the intervention arm complained of increased flatulence. No other safety issues were noted. CONCLUSION: Synbiotics could be available, safe, and an effective therapeutic strategy we could use in daily practice in order to decrease levels of uremic toxins and microinflammation in chronic kidney disease patients.

Presence of Non-Diabetic Kidney Diseases in Biopsy Specimens of Diabetic Patients' Single Center Experience.

The complications of type 2 diabetes mellitus (T2DM) are well known and one of them is diabetic chronic kidney disease (DCKD). Over time, it has become clear that patients with T2DM can have nondiabetic chronic kidney diseases (NDCKD), especially those that affect the glomeruli. Clinical indicators for identifying DCKD from NDCKD with high sensitivity and specificity have not yet been identified. Therefore, kidney biopsy remains the golden standard for DCKD diagnosis in patients with T2DM. Despite some indications for kidney biopsy, criteria for a biopsy differ between countries, regions, and doctors. The aim of the study was to analyze the biopsy findings in our T2DM population and the justification of the biopsy according to widely accepted criteria. This single center retrospective study analyzed data from 74 patients with T2DM who underwent kidney biopsy from January 2014 to January 2021. According to the biopsy data, we categorized31 patients in the DN group, patients with typical diabetic glomerulopathy, 11 patients in the mixed group, patients who had pathohistological elements for both DN and non-DN glomerulopathy, and 32 patients in the non-DN group, patients with primary glomerulopathy not linked with DM. In the non-DN and mixed groups, the most frequent glomerulopathy was mesangioproliferative glomerulonephritis, including IgA and non-IgA forms, found in 10 patients, and membranous nephropathy (MN) in 10 patients. We analyzed several parameters and only the amount of proteinuria was found to be significantly linked to biopsy findings related to DN. With the existing criteria for kidney biopsy, we managed to detect changes in the kidneys in about half of our patients with T2DM. These patients required specific treatment, different from that which we use for DCKD patients.

An unusual cause of rapidly progressive glomerulonephritis associated with ANCA vasculitis and ovarian malignancy - a relapse 39 years after initial treatment.

A 69-year-old woman presented with severe anemia, proteinuria, microscopic hematuria and rapidly progressive renal failure. She was admitted to the nephrology department due to severe deterioration of renal function with complaints of malaise, fever, dry cough and occasional epistaxis that appeared 2 months prior to admission. Histopathologic examination of a specimen from kidney biopsy and immunologic findings revealed ANCA positive pauci-immune crescentic glomerulonephritis. The patient had a history of ovarian granulosa cell tumor and lung metastases that were treated surgically with postoperative radiotherapy and chemotherapy. Thoracic computed tomography showed tissue neoplasm in the right lung and ultrasound-guided percutaneous transthoracic biopsy confirmed granulosa cell tumor. That was a relapse, thirty-nine years after initial treatment of malignant disease and twenty-four years after surgical resection of metastases from both lungs. Although the association between malignancy and vasculitis has been well known for decades, this is the first described case of ANCA vasculitis associated with any type of gynecological malignancy and glomerulonephritis.

Roxadustat for the treatment of anemia in chronic kidney disease patients not on dialysis: a Phase 3, randomized, double-blind, placebo-controlled study (ALPS).

BACKGROUND: Roxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of chronic kidney disease (CKD) anemia. METHODS: This Phase 3, multicenter, randomized, double-blind, placebo-controlled study examined patients with Stages 3-5 CKD, not on dialysis (NCT01887600). Patients were randomized (2:1) to oral roxadustat or placebo three times weekly for 52-104 weeks. This study examined two primary efficacy endpoints: European Union (European Medicines Agency)-hemoglobin (Hb) response, defined as Hb ≥11.0 g/dL that increased from baseline (BL) by ≥1.0 g/dL in patients with Hb >8.0 g/dL or ≥2.0 g/dL in patients with BL Hb ≤8.0 g/dL, without rescue therapy, during the first 24 weeks of treatment; US Food and Drug Administration-change in Hb from BL to the average Hb level during Weeks 28-52, regardless of rescue therapy. Secondary efficacy endpoints and safety were examined. RESULTS: A total of 594 patients were analyzed (roxadustat: 391; placebo: 203). Superiority of roxadustat versus placebo was demonstrated for both primary efficacy endpoints: Hb response [odds ratio = 34.74, 95% confidence interval (CI) 20.48-58.93] and change in Hb from BL [roxadustat - placebo: +1.692 (95% CI 1.52-1.86); both P < 0.001]. Superiority of roxadustat was demonstrated for low-density lipoprotein cholesterol change from BL, and time to first use of rescue medication (both P < 0.001). The incidences of treatment-emergent adverse events were comparable between groups (roxadustat: 87.7%, placebo: 86.7%). CONCLUSIONS: Roxadustat demonstrated superior efficacy versus placebo in terms of both Hb response rate and change in Hb from BL. The safety profiles of roxadustat and placebo were comparable.

Sodium thiosulphate and progression of vascular calcification in end-stage renal disease patients: a double-blind, randomized, placebo-controlled study.

BACKGROUND: Sodium thiosulphate (NaTS) is mostly used in haemodialysis (HD) patients with calcific uraemic arteriolopathy. This double-blind, randomized, placebo-controlled study assessed the effect of NaTS on progression of cardiovascular calcifications in HD patients. METHODS: From 65 screened patients, we recruited 60 patients with an abdominal aorta Agatston calcification score ≥100. Thirty patients were randomized to receive NaTS 25 g/1.73 m2 and 30 patients to receive 100 mL of 0.9% sodium chloride intravenously during the last 15 min of HD over a period of 6 months. The primary endpoint was the absolute change of the abdominal aortic calcification score. RESULTS: The abdominal aortic calcification score and calcification volume of the abdominal aorta increased similarly in both treatment groups during the trial. As compared with the saline group, patients receiving NaTS exhibited a reduction of their iliac artery calcification score (-137 ± 641 versus 245 ± 755; P = 0.049), reduced pulse wave velocity (9.6 ± 2.7 versus 11.4 ± 3.6; P = 0.000) and a lower carotid intima-media thickness (0.77 ± 0.1 versus 0.83 ± 00.17; P = 0.033) and had better preservation of echocardiographic parameters of left ventricular hypertrophy. No patient of the NaTS group developed new cardiac valve calcifications during the trial as compared with 8 of 29 patients in the saline group. By univariate analysis, NaTS therapy was the only predictor of not developing new valvular calcifications. No adverse events possibly related to NaTS infusion were noted. CONCLUSIONS: While NaTS failed to retard abdominal aortic calcification progress, it positively affected calcification progress in iliac arteries and heart valves as well as several other cardiovascular functional parameters.

Markers of Oxidative Stress and Endothelial Dysfunction Predict Haemodialysis Patients Survival.

INTRODUCTION: Overall survival of patients with end-stage renal disease (ESRD) remains poor. Oxidative stress is one of the major risk factors associated with mortality in this patient group. As glutathione S-transferases (GST) are well-established antioxidants, we hypothesized that a model including GST gene polymorphisms, oxidative damage byproducts and cell adhesion markers has a prognostic role in ESRD patient survival. METHODS: A prospective study of 199 patients with ESRD on haemodialysis was conducted. GST genotype, oxidative stress byproducts and cell adhesion molecules were measured in plasma. Multivariate Cox regression and Kaplan-Meier survival analyses were performed to test the predictive ability of these parameters in the 8-year follow-up period. RESULTS: GSTM1-null genotype was associated with significantly shorter overall (HR 1.6, p = 0.018) and cardiovascular-specific (HR 2.1, p = 0.010) survival. Oxidative stress byproducts (advanced oxidation protein products [AOPP], prooxidant-antioxidant balance [PAB], malondialdehyde [MDA]) and cell adhesion molecules (soluble vascular cell adhesion molecule-1 [sVCAM-1] and soluble intercellular adhesion molecule-1 [sICAM-1]) demonstrated a significant predictive role in terms of overall and cardiovascular survival. When 6 biomarkers (GSTM1 genotype, high AOPP/PAB/MDA/-sVCAM-1/sICAM-1) were combined into a scoring model, a significantly shorter overall and cardiovascular survival was observed for patients with the highest score (p < 0.001). CONCLUSION: We identified a novel panel of biomarkers that can be utilized in predicting survival in ESRD patients. This biomarker signature could enable better monitoring of patients and stratification into appropriate treatment groups.

Prevalence, clinical characteristics, and predictors of peripheral arterial disease in hemodialysis patients: a cross-sectional study.

BACKGROUND: Peripheral arterial disease (PAD) is common in patients with end-stage renal disease on hemodialysis, but is frequently underdiagnosed. The risk factors for PAD are well known within the general population, but they differ somewhat in hemodialysis patients. This study aimed to determine the prevalence of PAD and its risk factors in patients on hemodialysis. METHODS: This cross-sectional study included 156 hemodialysis patients. Comorbidities and laboratory parameters were analyzed. Following clinical examinations, the ankle-brachial index was measured in all patients. PAD was diagnosed based on the clinical findings, ankle-brachial index < 0.9, and PAD symptoms. RESULTS: PAD was present in 55 of 156 (35.3%; 95% CI, 27.7-42.8%) patients. The patients with PAD were significantly older (67 ± 10 years vs. 62 ± 11 years, p = 0.014), more likely to have diabetes mellitus (p = 0.022), and anemia (p = 0.042), and had significantly lower serum albumin (p = 0.005), total cholesterol (p = 0.024), and iron (p = 0.004) levels, higher glucose (p = 0.002) and C-reactive protein (p < 0.001) levels, and lower dialysis adequacies (p = 0.040) than the patients without PAD. Multivariate analysis showed higher C-reactive protein level (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.00-1.06; p = 0.030), vascular access by Hickman catheter (OR, 4.66; 95% CI, 1.03-21.0; p = 0.045), and symptoms of PAD (OR, 5.20; 95% CI, 2.60-10.4; p < 0.001) as independent factors associated with PAD in hemodialysis patients. CONCLUSION: The prevalence of PAD was high among patients with end-stage renal disease on hemodialysis. Symptoms of PAD, higher C-reactive protein levels, and Hickman vascular access were independent predictors of PAD in patients on hemodialysis.

Clot Structure: A Potent Mortality Risk Factor in Patients on Hemodialysis.

Patients with CKD on hemodialysis exhibit increased cardiovascular risk. Fibrin clot structure and clot lysis are crucially involved in development of cardiovascular events, but little is known about the influence of clot density on outcome in patients on hemodialysis. We determined fibrin clot structure parameters and effect on mortality in a prospective cohort of 171 patients on chronic hemodialysis (mean±SD age =59±11 years old; 54% men) using a validated turbidimetric assay. Kaplan-Meier analysis revealed that patients on hemodialysis with a denser clot structure had increased all-cause and cardiovascular mortality risks (log rank P=0.004 and P=0.003, respectively). Multivariate Cox regression models (adjusted for age, diabetes, sex, and duration of dialysis or fibrinogen, C-reactive protein, and complement C3) confirmed that denser clots are independently related to mortality risk. We also purified fibrinogen from healthy controls and patients on hemodialysis using the calcium-dependent IF-1 mAb against fibrinogen for additional investigation using mass spectrometric analysis and electron microscopy. Whereas purified fibrinogen from healthy controls displayed no post-translational modifications, fibrinogen from patients on hemodialysis was glycosylated and guanidinylated. Clots made of purified fibrinogen from patients on hemodialysis exhibited significantly thinner fibers compared with clots from fibrinogen of control individuals (mean±SD =63±2 and 77±2 nm, respectively; P<0.001). In vitro guanidinylation of fibrinogen from healthy subjects increased the formation of thinner fibers, suggesting that difference in fiber thickness might be at least partially due to post-translational modifications. Thus, in patients on hemodialysis, a denser clot structure may be a potent independent risk factor for mortality.

The 5A Allele of the MMP3-Gene Promoter Polymorphism Is a Risk Factor for Poor Outcome of Hemodialysis Patients.

Cardiovascular morbidity is the leading cause of death in dialysis patients and many risk factors have been involved in its pathogenesis. Genetic susceptibility may be of importance including polymorphism for matrix metalloproteinase 3 (MMP3), which is an enzyme that catalyzes the degradation of collagen, proteoglycans, fibronectin, laminine and elastin. The MMP3 gene promoter contains an insertion/deletion polymorphism characterised by an array of 5 or 6 adenosine residues (5A/6A) at -1612 position. Literature data show that the 5A or 6A allele of the MMP3 gene shows different risk for cardiovascular and overall outcome in general population. The aim was to analyze the -1612 5A/6A promoter polymorphism in a group of hemodialysis patients and to correlate the findings with cardiovascular morbidity and 7-year all-cause and cardiovascular mortality. This study included 196 patients on hemodialysis for longer than six months at University Medical Center Zvezdara. The leading causes of end stage renal disease were hypertension and diabetes mellitus. Venous blood was collected on midweek dialysis session and genotype analysis was performed by using polymerase chain reaction-restriction fragment length polymorphism method. Among the 198 hemodialysis patients, there were 142 (72%) 5A/6A heterozygotes, 12 (6%) 5A/5A homozygotes, and 44 (22%) 6A/6A homozygotes. These data are consistent with Hardy-Weinberg equilibrium. After 7-year follow-up, the 5A homozygotes showed the lowest all-cause and cardiovascular survival, while the 6A homozygotes showed the highest cardiovascular survival. The 5A allele of the MMP3-gene promoter polymorphism is a potential risk factor in the poor outcome of hemodialysis patients.

Long-Term Evaluation of Colestilan in Chronic Kidney Disease Stage 5 Dialysis Patients with Hyperphosphataemia.

BACKGROUND: This study investigated in a North American patient population the longer-term treatment effects of the phosphate binder, colestilan, in patients with CKD Stage 5D and hyperphosphataemia. METHODS: One hundred and sixteen CKD Stage 5D patients with hyperphosphataemia were entered into a multi-centre, open-label study where they received flexible dose colestilan (6-15 g/day) to maintain serum phosphorus levels between 3.5 and 5.5 mg/dl. The primary endpoint was safety, assessed by treatment-emergent adverse events. Efficacy was assessed by changes in serum phosphorus, mineral metabolism, lipids, HbA1c, uric acid and bone markers. RESULTS: Serum phosphorus was significantly reduced by 1.18 mg/dl (p < 0.001), from 6.99 mg/dl at baseline to 5.80 mg/dl at week 52. LDL-cholesterol was also significantly reduced as well as uric acid. Significant change was observed only for one bone marker - PINP. Most adverse events were of mild or moderate intensity. Nausea (22.4%), vomiting (21.6%), and diarrhoea (19.8%) were most commonly reported. CONCLUSIONS: Long-term flexible dosing with colestilan reduces serum phosphorus and demonstrates an acceptable safety and tolerability profile.

The effects of colestilan versus placebo and sevelamer in patients with CKD 5D and hyperphosphataemia: a 1-year prospective randomized study.

BACKGROUND: This study compared the effects of short-term titrated colestilan (a novel non-absorbable, non-calcium, phosphate binder) with placebo, and evaluated the safety and efficacy of colestilan over 1 year compared with sevelamer, in patients with chronic kidney disease (CKD) 5D. METHODS: This prospective multicentre study comprised a 4-week phosphate binder washout period, a 16-week short-term, flexible-dose, treatment period (including a 4-week placebo-controlled withdrawal period) and a 40-week extension treatment phase. RESULTS: At Week 16 (the end of the 4-week placebo-controlled withdrawal period), serum phosphorus level was 0.43 mmol/L (1.32 mg/dL) lower with colestilan than placebo (P < 0.001; primary end point). Serum LDL-C level was also lower with colestilan than with placebo (P < 0.001). Both colestilan and sevelamer produced significant reductions from baseline in serum phosphorus levels (P < 0.001), maintained for 1 year, and the proportion of patients achieving target levels of ≤1.78 mmol/L (5.5 mg/dL) or ≤1.95 mmol/L (6.0 mg/dL) at study end were similar (65.3 and 73.3%, respectively, for colestilan, and 66.9 and 77.4%, respectively, for sevelamer). Serum calcium level remained stable in the colestilan group but tended to increase slightly in the sevelamer group (end-of-study increase of 0.035 mmol/L over baseline). Both binders produced similar reductions from baseline in LDL-C level (P < 0.001), and responder rates after 1 year, using a target of <1.83 mmol/L (70 mg/dL) or <2.59 mmol/L (100 mg/dL) were similar in both groups (50.7 and 85.3% for colestilan and 54.0 and 80.6% for sevelamer). Colestilan was generally well tolerated. CONCLUSIONS: Colestilan is effective and safe for the treatment of hyperphosphataemia in patients with CKD 5D, and affords similar long-term phosphorus and cholesterol reductions/responder rates to sevelamer.

Associations of GSTM1*0 and GSTA1*A genotypes with the risk of cardiovascular death among hemodialyses patients.

BACKGROUND: The presence of glutathione transferase (GST) M1 null genotype (GSTM1-null) in end-stage renal disease (ESRD) patients is associated with lower overall survival rate in comparison to those with GSTM1-active variants. We examined association between GSTM1 and GSTT1 deletion polymorphisms as well as SNPs in GSTA1/rs3957357 and GSTP1/rs1695 genes with overall and cause-specific cardiovascular mortality in ESRD patients. METHODS: Total of 199 patients undergoing hemodialysis were included in the study. Median value of time elapsed from dialysis initiation until the death, or the end of follow-up was 8 ± 5 years. The effect of GSTM1, GSTT1, GSTP1 and GSTA1 gene polymorphisms on predicting overall and specific cardiovascular outcomes (myocardial infarction, MI or stroke) was analyzed using Cox regression model, and differences in survival were determined by Kaplan-Meier. RESULTS: GSTM1-null genotype in ESRD patients was found to be independent predictor of overall and cardiovascular mortality. However, after false discovery rate and Bonferroni corrections this effect was lost. The borderline effect modification by wild-type GSTA1*A/*A genotype on associations between GSTM1-null and analyzed outcomes was found only for death from stroke. Homozygous carriers of combined GSTM1*0/GSTA1*A genotype exhibited significantly shorter time to death of stroke or MI in comparison with carriers of either GSTM1-active or at least one GSTA1*B gene variant. The best survival rate regarding cardiovascular outcome was found for ESRD patients with combined GSTM1-active and mutant GSTA1*B/*B genotype. CONCLUSIONS: Combined GSTM1*0/GSTA1*A genotypes might be considered as genetic markers for cardiovascular death risk in ESRD patients, which may permit targeting of preventive and early intervention.

Evaluation of colestilan in chronic kidney disease dialysis patients with hyperphosphataemia and dyslipidaemia: a randomized, placebo-controlled, multiple fixed-dose trial.

BACKGROUND: Colestilan is a non-absorbed, non-calcium-based, phosphate binder. It also binds bile acids and reduces serum levels of low-density lipoprotein cholesterol (LDL-C). This study evaluated the efficacy of a range of fixed doses of colestilan compared with placebo for the control of serum phosphorus and LDL-C levels in patients with CKD stage 5 on dialysis. METHODS: This was a multicentre, randomized, double-blind, placebo-controlled, multiple fixed-dose trial in which 642 patients with CKD stage 5 on dialysis who had both hyperphosphataemia and dyslipidaemia, were randomized to treatment with colestilan 3, 6, 9, 12 or 15 g/day or placebo for 12 weeks. The co-primary endpoints were the mean changes in serum phosphorus and the mean per cent change in LDL-C from baseline to Week 12. RESULTS: A significantly greater mean reduction in serum phosphorus level from baseline to Week 12 than seen with placebo was seen with 9 g (-0.28 mmol/L) and pooled colestilan 12/15 g (-0.34 mmol/L). The per cent reduction in LDL-C level was significantly greater with colestilan 3, 6 and 9 g and pooled colestilan 12/15 g than with placebo (reduction ranged from 15.9 to 27.6% dependent on dose). Colestilan also reduced total cholesterol, oxidized LDL-C, HbA1c and uric acid levels, and did not increase serum calcium levels. Colestilan was generally well tolerated; the most common adverse events affected the gastrointestinal system. CONCLUSIONS: Colestilan is an effective treatment for hyperphosphataemia, and provides beneficial effects on other metabolic parameters associated with cardiovascular risk, notably LDL-C.

Glutathione S-transferase A1, M1, P1 and T1 null or low-activity genotypes are associated with enhanced oxidative damage among haemodialysis patients.

BACKGROUND: Increased oxidative stress is a hallmark of end-stage renal disease (ESRD). Glutathione S-transferases (GST) are involved in the detoxification of xenobiotics and protection of oxidative damage. We hypothesized that genetic polymorphism in antioxidant enzymes GSTA1, GSTM1, GSTP1 and GSTT1 is more frequent in ESRD and modulates the degree of oxidative stress in these patients. METHODS: GSTA1, GSTM1, GSTP1 and GSTT1 genotypes were determined in 199 ESRD patients and 199 age- and gender-matched controls. Markers of protein and lipid oxidative damage [thiol groups, carbonyl groups, advanced oxidative protein products, nitrotyrosine, malondialdehyde (MDA) and MDA adducts], together with total oxidant status and pro-oxidant-antioxidant balance were determined. RESULTS: Individual GST polymorphisms influence vulnerability to both protein and lipid oxidation, with GSTM1-null gene variant having the most pronounced effect. Furthermore, a strong combined effect of null/low-activity GSTM1, GSTT1, GSTA1 and GSTP1 genotypes in terms of susceptibility towards oxidative and carbonyl stress was found in ESRD patients. When patients were stratified according to GSTM1 and GSTT1, the highest oxidant damage was noted in those with the GSTM1-null/GSTT1-null genotype. The observed effect was even stronger in patients with the third low-activity GSTP1 or GSTA1 genotype. Finally, the level of oxidative and carbonyl stress was most pronounced in the subgroup of patients with all four null or low-activity GSTM1, GSTT1, GSTP1 and GSTA1 genotypes. CONCLUSIONS: According to the GST genotype, ESRD patients may be stratified in terms of the level of oxidative and carbonyl stress that might influence cardiovascular prognosis, but could also improve efforts towards individualization of antioxidant treatment.

Arteriovenous fistula aneurysm in patients on regular hemodialysis: prevalence and risk factors.

BACKGROUND/AIMS: Compared to all other complications, literature data about vascular access aneurysm (VAA) are the scarcest. The aim of this cross-sectional study was to evaluate the prevalence of arteriovenous fistula (AVF) aneurysms and to confirm the risk factors for their appearance. METHODS: The presence, number and morphological characteristics of AVF aneurysms were confirmed, and according to the score of AVF aneurysm (the sum of the length and width in cm), patients were classified into group 1 (score ≤12) and group 2 (score >12). Analysis included the last data from the medical records including vascular calcifications score. RESULTS: Out of 181 patients, 150 with native fistula were included in this study. Aneurysmatic changes were detected in 90 (60%) patients, and the majority had two or more aneurysms. VAA were more frequent in patients with adult polycystic kidney disease (ADPKD) than in other diagnostic categories. By using forward stepwise logistic regression, we confirmed that patients on high-flux hemodialysis (HD) had 5.3-fold higher risk, and patients with diabetes mellitus had 5.8-fold less risk for developing AVF aneurysm. While vascular calcification score did not influence the incidence of VAA, higher PWV had significant negative influence on formation of AVF aneurysm (OR 1.25, 95% CI 1.003-1.56, p = 0.047). By ROC curve analysis, it was determined that patients who were longer than 5.7 years on HD had greater risk for developing VAA (area = 0.741, p = 0.000). CONCLUSION: This single-center study confirmed the very high prevalence of VAA (60%). Aneurysms were more frequent in patients with ADPKD and in those who had longer dialysis vintage on high-flux membranes with higher blood flow rate.

Safety of Roxadustat Versus Erythropoiesis-Stimulating Agents in Patients with Anemia of Non-dialysis-Dependent or Incident-to-Dialysis Chronic Kidney Disease: Pooled Analysis of Four Phase 3 Studies.

INTRODUCTION: This study was conducted to elucidate the safety of roxadustat, an oral medication, in patients with non-dialysis-dependent (NDD) or incident dialysis dialysis-dependent (ID-DD) chronic kidney disease (CKD). METHODS: Safety results from four phase 3, randomized, open-label studies comparing roxadustat to an erythropoiesis-stimulating agent (ESA) in men and women with NDD or ID-DD CKD with anemia were pooled and evaluated. Endpoints were time to major adverse cardiovascular event (MACE; myocardial infarction, stroke, and all-cause mortality) and MACE+ (MACE plus congestive heart failure or unstable angina requiring hospitalization), all-cause mortality, and treatment-emergent adverse events (TEAEs). MACE and MACE+ were evaluated for non-inferiority at 1.8- and 1.3-margins using hazard ratios (HRs) and 95% confidence intervals (CIs). TEAEs were descriptively summarized. RESULTS: In total, 2142 patients were evaluated (1083 roxadustat; 1059 ESA). Roxadustat was comparable to ESA for risk of MACE (HR 0.79, 95% CI 0.61-1.02), MACE+ (HR 0.78, 95% CI 0.62-0.98), and all-cause mortality (HR 0.78, 95% CI 0.57-1.05). TEAEs were comparable between roxadustat and ESA groups, including any TEAE [incidence rate per 100 (IR/100) patient-exposure years 56.1 vs. 53.5], TEAEs leading to study drug discontinuation (IR/100 patient-exposure years 6.7 vs. 5.1), and TEAEs leading to death (IR/100 patient-exposure years 6.9 vs. 7.4). CONCLUSION: There was no evidence of increased risk of cardiovascular events or mortality with roxadustat compared with ESA in patients with anemia who have NDD or ID-DD CKD. Although TEAEs occurred commonly in both the roxadustat and ESA groups, patients infrequently discontinued the study drug because of an adverse event. CLINICAL TRIAL REGISTRATION NUMBERS: DOLOMITES, 1517-CL-0610 [NCT02021318]; HIMALAYAS, FGCL-4592-063 [NCT02052310]; SIERRAS, FGCL-4592-064 [NCT02273726]; and ROCKIES, D5740C00002 [NCT02174731].

Screening of elderly for chronic kidney disease.

BACKGROUND AND AIMS: The frequency of chronic kidney disease (CKD) markers was assessed in two groups of patients over 60 years--one without and the other with hypertension. METHODS: The cross-sectional study involved 585 asymptomatic elderly patients (227 males), 93 without and 492 with hypertension. Data on patients were obtained by interview, analysis of medical records and physical examinations. Serum and urine creatinine, proteinuria, microalbuminuria (MAU, turbidimetry), and urinary sediment were analyzed. RESULTS: Among the 585 patients, there were 54.5% with a positive family history for hypertension and 14% for kidney diseases. MAU was significantly more frequent (30 vs. 11%) and the mean estimated glomerular filtration rate (eGFR) higher (71 ± 14 vs. 64 ± 14 ml/min/1.73 m) in patients without hypertension than in those with hypertension. The majority of patients with stage 3 CKD had eGFR >45 ml/min/1.73 m(2) with normal urinary findings. Multivariate logistic regression analysis found age and treatment with angiotensin-converting enzyme inhibitors to be associated with reduced eGFR, MAU and proteinuria. In addition, smoking was associated with eGFR, but a family history for kidney disease and belonging to the group without hypertension were associated with MAU. CONCLUSION: The high prevalence of markers for CKD in symptomless elderly without hypertension confirmed that the elderly, as a high-risk population, should be screened based on increased age alone.

Circulating nonphosphorylated carboxylated matrix gla protein predicts survival in ESRD.

The mechanisms for vascular calcification and its associated cardiovascular mortality in patients with ESRD are not completely understood. Dialysis patients exhibit profound vitamin K deficiency, which may impair carboxylation of the calcification inhibitor matrix gla protein (MGP). Here, we tested whether distinct circulating inactive vitamin K-dependent proteins associate with all-cause or cardiovascular mortality. We observed higher levels of both desphospho-uncarboxylated MGP (dp-ucMGP) and desphospho-carboxylated MGP (dp-cMGP) among 188 hemodialysis patients compared with 98 age-matched subjects with normal renal function. Levels of dp-ucMGP correlated with those of protein induced by vitamin K absence II (PIVKA-II; r = 0.62, P < 0.0001). We found increased PIVKA-II levels in 121 (64%) dialysis patients, indicating pronounced vitamin K deficiency. Kaplan-Meier analysis showed that patients with low levels of dp-cMGP had an increased risk for all-cause and cardiovascular mortality. Multivariable Cox regression confirmed that low levels of dp-cMGP increase mortality risk (all-cause: HR, 2.2; 95% CI, 1.1 to 4.3; cardiovascular: HR, 2.7; 95% CI, 1.2 to 6.2). Furthermore, patients with higher vascular calcification scores showed lower levels of dp-cMGP. In 17 hemodialysis patients, daily supplementation with vitamin K2 for 6 weeks reduced dp-ucMGP levels by 27% (P = 0.003) but did not affect dp-cMGP levels. In conclusion, the majority of dialysis patients exhibit pronounced vitamin K deficiency. Lower levels of circulating dp-cMGP may serve as a predictor of mortality in dialysis patients. Whether vitamin K supplementation improves outcomes requires further study.

Biomarkers and Predictors of Adverse Cardiovascular Events in Different Stages of Chronic Kidney Disease.

Chronic kidney disease (CKD) is an important factor that contributes to the increase of all-cause morbidity and mortality in the group of non-communicable diseases, and it is also recognized as a strong and independent risk factor that contributes to cardiovascular disease (CVD). CVDs are a consequence of the action of a large number of risk factors among which are traditional and non-traditional. These risk factors have been the subject of a large number of studies which partially explained the unfavorable cardiovascular (CV) outcome of CKD patients. Therefore, valid studies about clinical and biohumoral predictors are of particular importance, especially in the early stages of renal disease, that is, in patients with creatinine clearance below 60 ml/min/1.73 m2 when preventive measures are most effective. Among potential predictors of adverse CV outcome are biomarkers of inflammation (Interleukin-18-IL-18), oxidative stress (ischemia-modified albumin-IMA; superoxide dismutase-SOD), acute kidney injury (kidney injury molecule-1-KIM-1; neutrophil gelatinase-associated lipocalin-NGAL), and microribonucleic acids (specific microRNA-133a). In this review, we tried to confirm the relationship between risk factors of CKD and CVD and newer, less frequently examined biomarkers with the occurrence of incidental CV events in renal patients.

Gender-specific differences in hemodialysis patients: a multicenter longitudinal study from Serbia.

PURPOSE: The study was undertaken with the aim to determine gender-specific differences in incident hemodialysis (HD) patient and their changes over time. METHODS: The retrospective longitudinal closed cohort study involved 441 incident patients starting HD in 2014 and followed for 1-59 (median 43, IQR 40) months. Demographic, clinical data, treatment characteristics, laboratory findings and outcome were abstracted from the patients' medical records. RESULTS: The relative number of males on HD was about twice that of females throughout the five years investigated. At the beginning of the study, no significant differences were found in the main demographic and clinical characteristics except that diabetes was more often the underlying disease in men than in women. Systolic blood pressure decreased over time significantly more in females than in males. Throughout the study spKt/V was significantly higher in females than in males, but it increased in patients of both genders. There were no gender differences for comorbidities, vascular access and the majority of laboratory findings except for higher serum levels of creatinine and CRP in men than in women. Relatively more females were treated with erythropoiesis stimulating agents and phosphate binders than males. Age and malignancy were selected as significant predictors of mortality for both genders, and, in addition, polycystic kidney disease, serum level of albumin and CRP for men, but spKt/V for women. CONCLUSION: Some significant gender differences were observed throughout, while others appeared during the study but none of them were due to gender inequalities in the applied treatment.